In the current budget period, the Adult Children Study (ACS) transitioned from cross-sectional to longitudinal analyses, many of which are ongoing. With this application, the ACS now incorporates new biomarkers to address the overarching hypothesis that disrupted neural integrity is the proximate cause of the transition from preclinica to symptomatic Alzheimer disease (AD). Two corollary hypotheses will be addressed: 1) cerebral amyloidosis and tauopathy individually are necessary but insufficient to cause the transition from cognitive normality to impairment; and 2) the spread of tauopathy from the medial temporal lobe to the neocortex is the tau imaging correlate of the transition from preclinical to symptomatic AD. Predicting individual-level development of symptomatic AD will be enormously important for the field and may accelerate secondary prevention trials of anti-AD therapies by permitting the enrollment of only cognitively normal individuals who have near certainty of progressing to symptomatic AD. The ACS investigators and its cohort are uniquely qualified to accomplish the following Specific Aims: 1. Recruit, enroll, and maintain the ACS cohort (N?300) 2. At entry and every 3 years thereafter comprehensively assess all participants with: 1) well-established clinical and cognitive instruments (annually for participants >65 years); 2) blood for genotyping for apolipoprotein E and other susceptibility genetic variants; 3) PET scans with amyloid and tau tracers (florbetapir and T807); 4) lumbar puncture (LP) for the collection of CSF; 5) an attentional battery; and 6) structural and functional MRI. 3. In ACS participants who transition from cognitive normality to impairment, correlate phenoconversion with: a. The regional distribution and density of tau retention (Project 1) b. CSF markers of neural (tau, p-tau181) and synaptic (SNAP-25, neurogranin) injury (Project 2) c. Longitudinal rates of change on measures of global cognition and episodic memory (Clinical Core, Project 1) and attentional control (Project 3), cross sectional event-related fMRI as a function of AD markers, and the relation among A?42, sleep, and memory consolidation mechanisms (Project 3) d. The regional distribution and density of amyloid retention, and changes in brain structure and function (hippocampal volume, cortical thickness, functional connectivity) (Project 4) e. CSF concentrations of A?42, and also novel analytes (YKL-40, VILIP 1) (Project 2) 4. Analyze associations among rates of change of all AD markers from all Cores and Projects (Data Management and Biostatistics Core).